Device and method for detecting the coagulation functions of global, especially primary hemostasis

ABSTRACT

The invention relates to a method and to a device for examining the properties of the global, in particular the primary, hemostasis functions in whole blood or platelet-rich plasma, comprising  
     a storage chamber ( 15 ) for the blood to be examined,  
     a reaction device ( 39 ) having at least one flow path ( 5, 16 ) via which the blood to be examined is transported for carrying out certain reactions,  
     a conveyor device ( 1 ) which conveys a volumetric flow for the transport of the blood through the reaction device ( 39 ), thereby generating a conveyor pressure,  
     a pressure gauge ( 8, 9 ) which in a blood-free pressure gauge chamber ( 3 ) measures changes in the conveyor pressure which appear depending on the reactions of the blood to be examined which have taken place in the reaction device ( 39 ),  
     a blood collection chamber ( 10 ) for collecting the blood transported through the reaction device ( 39 ),  
     the conveyor pressure in a pressure-sealed working chamber ( 12 ) being generated by a piston-cylinder system ( 1 ),  
     a working surface ( 33 ) of the piston ( 4 ) forming a boundary of the working chamber ( 12 ), and  
     the working chamber ( 12 ) being formed by the blood collection chamber ( 10 ) and the blood-free pressure gauge chamber ( 3 ).  
     According to the method of the invention, the volumetric flow is preferably adjusted, depending on the measured pressure of the volumetric flow, in such a way that the shear rate or the shear force, whose action in the reaction opening causes blood components, in particular thrombocytes, to deposit, follows a predetermined characteristic curve and in particular is held constant.

DESCRIPTION

[0001] The invention relates to a device according to the preamble ofclaim 1 and to a method according to the preamble of claim 58.

PRIOR ART

[0002] Such a method and such a device are known from German PatentApplication 196 17 407 A1, in which a volumetric flow of blood to beexamined is transported from a storage vessel through a flow path,designed as an aperture, of a reaction device by means of apiston-cylinder system. The aperture becomes increasing blocked byaggregation and/or coagulation of blood components, particularlythrombocytes. The resulting pressure drop at the outlet side of theaperture is detected and measured in a pressure gauge chamber free ofblood to be examined, via a supply line to a pressure sensor. Thepressure gauge chamber is situated below the piston surface of thevertically upwardly moved piston adjoining the working chamber of thepiston-cylinder system. The blood to be examined is thus upwardlyconveyed from a storage chamber located below the aperture. The pressuregauge chamber is situated between the surface of the blood conveyedthrough the aperture and the underside of the piston. The pressure inthe pressure gauge chamber is sampled and measured via the supply linewhich leads through the piston and which is connected to the pressuresensor.

[0003] In addition, a method and a device are known from European PatentApplication 0 635 720 A1 in which the deposition or aggregation ofthrombocytes is initiated under specified flow conditions. As the resultof rotational movement with respect to a surface which the blood to beexamined undergoes, shear forces appear on the surface. Thrombocytesdeposit on the base of the container in which the blood to be examinedis situated. The deposited thrombocytes are then evaluated by electronmicroscope scanning, optical image analysis, or the like.

[0004] In addition, it is known from European Patent 0 138 190 B1 thatin a membrane opening through which a blood sample is transported,aggregation of thrombocytes can be initiated by shear forces in theopening (aperture). To measure the aggregation of the thrombocytes, theblood sample above the measurement aperture is subjected to pressure,and the time in which a specified reduction in the measurement apertureappears as the result of the aggregation of thrombocytes is measured.

[0005] In addition, a device is known from an article by Hubert Poliwodaet al., “Das Thrombometer: Seine Bedeutung als Globaltest zurBeurteilung der Thrombozytenfunktion” (The Thrombometer: Its Importanceas a Global Test for the Evaluation of the Thrombocyte Function) (Klin.Lab. June 1995, pp. 457-464), by which the reaction of thrombocytes canbe examined without unphysiological, mechanical, or chemical effects. Tothis end, whole blood is withdrawn from the vein of a patient using acannula connected to the reaction device. The reaction device includes acollagen plate having a precisely bored opening with a diameter of 0.5mm. The withdrawn blood flows through this opening with a velocity of 8cm/s, each thrombocyte passing through the opening in the collagen inapproximately 50 ms. A constant flow rate is forcibly maintained using amechanically operated pump connected to the reaction device. The bloodis aspirated at a velocity of 0.94 mL/min. The thrombocytes are detainedas they pass the collagen opening, thereby increasingly closing theborehole in the channel of the reaction device. The time in which thesuction pressure rises from 50 to 150 mbar is determined. In addition, adevice may be placed between the cannula and the reaction device whichcontinuously supplies the solution of a substance whose effect on thethrombocyte function on collagen may be tested. The pressure is measuredin a suction tube filled with 0.9% NaCl solution.

[0006] A measuring device is known from U.S. Pat. No. 5,662,107 by whichthrombus formation is measured in vitro under simulated in vivoconditions. To this end, blood is pumped at a constant flow rate througha channel which is made of a material promoting blood thrombosis orwhich is coated with such a material. The pressure is measured upstreamand downstream from the thrombus-forming unit, and the difference inpressure is evaluated as the tendency toward thrombus formation. Thisindicates the importance of the shear rate for the deposition ofplatelets and the activation of coagulation. Care must be taken,however, that as the deposition of platelets increases, the shear rateincreases unchecked when the flow rate is maintained.

OBJECT OF THE INVENTION

[0007] The object of the present invention is to provide a device and amethod of the aforementioned type by which exact and reproduciblemeasurement results are obtained at low measurement costs. For thedevice, this object is achieved by the characterizing features of claims1, 2, and 3, and for the method, the object is achieved by thecharacterizing features of claim 58.

[0008] A very economical measuring device is thus provided, using asimple and low-maintenance technique, which can apply to the measuringinserts as well. The device offers the requisite features for theinexpensive production of a multichannel automatic device for use inlarge-scale laboratories as well as for a small device having onemeasuring channel, for example, or for use under severe conditions inthe immediate vicinity of the patient (point of care). The method makesit possible to carry out the measurement run under controlled shearconditions in the changing reaction opening, and thus to form new,important diagnostic assays.

[0009] Whole blood or platelet-rich plasma can be used for themeasurements of coagulation functions of global, in particular primary,hemostasis. Sodium citrate, hirudine, and other substances may be usedas anticoagulants. To initiate coagulation, activators such as, forexample, collagen, adenosine diphosphate, thrombin, and other substanceslisted below may be present on the boundary surfaces of the reactionopenings, or they may be added to the blood sample before or during themeasurement.

[0010] According to the invention, the pressure gauge chamber issituated below the storage chamber, from which the blood to be examinedis conveyed. The reaction device is situated between the storage chamberand the pressure gauge chamber. After the blood passes through thereaction device, which may be situated underneath, for example in thebase region of the storage chamber, the blood to be examined is ledthrough the central flow opening and past the pressure gauge chamber toa pressure-sealed blood collection chamber, where it collects during themeasurement process. The pressure gauge chamber is situated above thesurface of the blood collected in the pressure-sealed blood collectionchamber. Preferably, a pressure which is proportional to or equal to theconveyor pressure prevails in the pressure gauge chamber. Apiston-cylinder drive system is preferably used to generate the conveyorpressure. To this end, the pressure gauge chamber may be situated in theworking chamber of the piston-cylinder system, in which the pressureprevailing for the blood to be conveyed through the reaction opening inthe measuring device is the conveyor pressure. The pressure in thepressure gauge chamber then corresponds to the conveyor pressure. Apiston surface, as a working surface, thereby forms the boundary of theworking chamber. The pressure gauge chamber is thus formed by thecylinder of the piston-cylinder system and one or multiple spacingmeans, in particular by a portion of the reaction device. Thepiston-cylinder system is preferably situated below a storage vessel inwhich the storage chamber is provided for the blood to be examined. Thepiston-cylinder system together with the expanding cylinder interior(working chamber) may form the blood collection chamber. However, asdiscussed below, the device which supplies the conveyor pressure, suchas the piston-cylinder system, for example, may also be situated outsidethe blood collection chamber.

[0011] To sample the pressure prevailing in the pressure gauge chamber,a pressure sensor which supplies corresponding signals may be arrangedin the pressure gauge chamber. Preferably, a pressure line such as ahollow needle is used which is guided through the wall of the pressuregauge chamber in a pressure-sealed manner and which is connected to apressure gauge, such as a pressure sensor, outside the pressure gaugechamber. The hollow needle preferably has a tip in the form of aninjection cannula on its end which is guided through the wall of thepressure gauge chamber. However, it is also possible to connect thepressure line, which is designed as a gas pressure line, to the pressuregauge chamber by using an integrally molded connector or other means.The wall enclosing the pressure gauge chamber is preferably made ofplastic so that this wall can be penetrated by the needle in order toinsert the end of the needle into the pressure gauge chamber in apressure-sealed manner. Preferably, an electrically actuated valve issituated in a branch of the gas pressure line by which air can betransported away by the movement of the conveyor piston in the measuringcylinder, for example, in order to reduce air pockets in the pressuregauge chamber.

[0012] The supply vessel and the cylinder of the piston-cylinder systemmay be produced as a single piece. The reaction device by which theblood is led through the central flow opening and past the pressuregauge chamber is situated in the region of the base of the supplyvessel.

[0013] In the measurement systems, the piston-cylinder system situatedunderneath may also be advantageously formed using a blood withdrawalsyringe containing anticoagulated blood withdrawn from patients, thepiston of which is connectable to drive 17 via a coupling. A hollowneedle attached in a pressure-sealed manner at its one end in thecentral flow opening penetrates the sealing insert in the upwardlypointing syringe adapter, thus connecting the blood collection chamber(or storage chamber) to the storage chamber (or blood collectionchamber) of the blood withdrawal syringe via the reaction device. Inthis embodiment, the blood storage chamber is formed in the workingchamber of the cylinder of the withdrawal syringe. The flow opening inthe hollow needle may be designed as a feed opening which preferablyacts as a shear opening.

[0014] Preferably, before the measurement is begun the piston is movedupward in the syringe cylinder in the direction toward the reactiondevice, pushing the blood column formed by the inner wall of thecylinder upward with its working surface, with bleeder valve 20 open,until the upper blood level is detected at a precisely defined positionby a level sensor which then signals the reference position to thecontrol unit, whereupon the measurement can begin. The referenceposition defines the volume of the air pocket which forms the blood-freepressure gauge chamber and which is bounded by the outside of the hollowneedle, the blood level, the inner wall of the syringe adapter, and theunderside of sealing insert 26. This type of design is particularlysuited for use in the immediate vicinity of the patient (point of care),because the complicated pipetting of the blood sample is omitted.

[0015] In the exemplary embodiments in which the conveyor device issituated outside the blood collection chamber, a pressure line,particularly a gas pressure line, which conducts the conveyor pressureis provided which is led in a pressure-sealed manner from the outsidethrough a container wall of the pressure-sealed collection chamber, intothe blood-free pressure gauge chamber. The container wall preferably ismade of plastic, particularly polyethylene, or another material whichduring insertion makes pressure-sealed contact with the outside of thepressure line. For this purpose, the pressure line is preferablydesigned as a hollow needle (cannula) having a tapering needle end. Thetapering needle end is pushed through the container wall into thepressure gauge chamber. The conveyor device may be designed in a knownmanner as a suction/pressure pump, piston-cylinder system, or the like,which in conjunction with the drive generates the conveyor pressure inthe pressure line.

[0016] Preferably, the pressure line led through the container wall ofthe storage chamber or the collection chamber conducts the conveyorpressure as well as the pressure to be measured. To this end, thepressure line is connected outside the container wall to a pressuregauge, in particular a pressure sensor, via a branched pressure gaugeline. The conveyor pressure corresponds to the pressure to be measuredwhich prevails in the blood-free pressure gauge chamber.

[0017] The reaction device is preferably situated above the collectionchamber, in a common housing with the collection chamber. In addition,the storage chamber above the reaction device may likewise be situatedin the common housing. To this end, the storage chamber and at leastportions of the reaction device as well as the collection chamber may beconstructed in one piece to form the common housing. However, theseparate reaction device may also be designed to be insertable into thecommon housing in a liquid-sealed manner.

[0018] The storage chamber may also be formed by the interior of thecylinder of a blood withdrawal syringe, the cylinder interior beingconnectable to the reaction device via a hollow needle. The hollowneedle may be designed as a cannula in the blood withdrawal syringewhich includes the storage chamber, which with its needle tip may beguided in a pressure-sealed manner from the outside to the reaction siteof the reaction device. For this purpose, the base material of thereaction device may be designed in such a way that after being puncturedby the hollow needle it makes self-sealing contact with the outside ofthe hollow needle. However, the hollow needle which leads to thereaction site of the reaction device may also be attached in apressure-sealed manner to the reaction device and pushed with its freeneedle end through a sealing wall of the top-mountable storage chamber,such as the cylinder interior of a syringe. The sealing wall of thestorage chamber is likewise made of a material, as previously described,which makes pressure-sealed contact with the hollow needle. The hollowneedle preferably forms the feed opening for the blood from the storagechamber to the reaction opening, and may also preferably act as theshear opening. This type of design is particularly suited for use in theimmediate vicinity of the patient (POC or point of care), because thecomplicated pipetting of the blood sample is omitted.

[0019] Various embodiments may be used for the reaction device.Preferably, an embodiment is used for detecting the coagulationproperties of the global, in particular also the primary, hemostasis, inwhich the blood to be examined may be conveyed to the blood collectionchamber by a conveyor device, in particular a piston-cylinder systemwhich can be driven by a drive device from a storage chamber, via one ormultiple reaction openings in the reaction device which may alsosimultaneously act as shear openings, to the blood collection chamber.Feed openings which may simultaneously act as shear openings may besituated upstream or downstream from the reaction opening(s), thesurfaces of the shear openings being hydrophobic to avoid deposition ofblood components at that location. The boundary areas of the reactionopenings may also have a hydrophobic design or be provided with aroughness sample. The boundary surfaces or partial surfaces of one ormultiple reaction openings or reaction sites on which blood componentsmay optionally deposit or react under the effect of shear forces may bemade of, for example, hydrophilic or optionally also hydrophobicplastic, glass, or porous or nonporous bioactive films/membranes, orcollagen membranes, or porous membranes (cellulose acetate, forexample), or may be coated with these materials, and additionally or asneeded may have a reactive design for various investigations of thecoagulation or platelet reaction by being bioactively coated,impregnated, or covered with, for example, thrombin or batroxobin, anextracellular matrix (ECM), collagen (also natural recombinant collagenor purified collagen subtypes), synthetic peptides having collagen-likeamino acid sequences, or laminin or fibronectin, preferablythrombospondin, erythrocytes and/or leucocytes, preferably of blood typeO or containing von Willebrand factor, or a mixture of collagen (asabove) or synthetic peptides with substances such as adenosinediphosphate (ADP), adrenalin, fibronectin, thrombospondin, and/or otheragents which induce the coagulation reaction (European PatentApplication 0 316 599 A2, European Patent 0 111 942, U.S. Pat. Nos.5,854,067, and 6,662,107).

[0020] In a blood vessel, the blood flow rate is inversely proportionalto the radius of the blood vessel, and is lower at the vessel wall thanin the center of the vessel. The difference in velocity betweenadjoining liquid layers flowing in parallel past one another produces ashear effect between these layers. This effect is greatest at the vesselwall, and diminishes toward the center of the vessel. The localizedshear rate corresponding to the velocity gradients between two adjoiningliquid layers flowing past one another affects the shear stress and isdirectly proportional to the velocity gradient. Correspondingly, variousshear rates prevail at the surface of the vessel walls in differenttypes of vessels. Physiological shear rates in large veins are <100 s⁻¹.For arteries, the wall shear rates vary between 100 and 1000 s⁻¹,depending on the diameter of the arteries, and in arterioles the shearrates reach approximately 1500 s⁻¹. In the coronary arteries the averageshear rate is approximately 650 s⁻¹. Extremely high shear rates ofapproximately 3000 s⁻¹ to a maximum of 40,000 s⁻¹ exist in vesselsconstricted by atherosclerosis. Depending on the magnitude of the shearstress, in certain types of cells, particularly thrombocytes, theexternal shapes and reactivities as well as the binding behavior of themembrane and plasma proteins are altered. It is known that as the shearrate rises, normal thrombocytes, in particular those which areactivated, increasingly adhere to collagen surfaces, for example, andthen aggregate (atherosclerosis). In contrast, platelets whose functionis inhibited by the effect of ASA (acetylsalicylic acid), for example,or by von Willebrand disease, adhere increasing less to collagensurfaces, for example, as the shear rate rises, and therefore aggregate(hemorrhage diathesis). This knowledge may be put to use according tothe invention for the sensitive diagnosis of platelet functions of theprimary hemostasis by moving a volumetric flow of blood in a controlledmanner so that, using an aperture or reaction opening coated withcollagen, for example, a predetermined, in particular constant, shearrate is maintained in the aperture or reaction opening which is growingsmaller or closing due to the deposition and aggregation ofthrombocytes. The volumetric flow of the blood to be examined whichpasses through the aperture/reaction opening may also be adjusted as afunction of any desired predetermined shear rate or shear forcecharacteristic curve.

[0021] The conveyor flow created by the regulated motion of the pistonin the piston-cylinder system generates a conveyor pressure which,corresponding to the flow resistance, builds up in the reactionopening(s). The bloodstream creates shear or flow conditions in thereaction opening(s) by whose action thrombocytes may adhere andaggregate, corresponding to their functionality, at the boundarysurfaces in the reaction openings(s) which are designed to be bioactiveor capable of deposition. The thrombocytes may thereby reduce the opencross section of the reaction opening or may completely close thisreaction opening by forming a thrombus, or, through the influence of thereactively designed boundary surface(s) of the reaction opening(s) orthrough the influence of supplied activators, result in a change in theblood flowability due to the onset of global blood coagulation, inparticular by an alteration in the physical structure of polymerizedfibrin and cellular components (platelets, erythrocytes, leucocytes) orby an increase in the force exerted on the fibrin network by activatedthrombocytes. This generates a variable pressure in the conveyance pathof the blood to be examined which is transported through the reactiondevice, this pressure acting in the pressure gauge chamber and beingapplied upstream or downstream from the reaction opening and being usedto regulate the conveyed volumetric flow. According to the invention,the volumetric flow is adjusted in such a way that, depending on theparticular measured pressure, the shear rate or shear force acting onthe reaction site or in the reaction opening follows a predeterminedcharacteristic curve which preferably corresponds to a constant shearrate/shear force, or which follows another predetermined curve for theshear rate or flow rate. The measurement and analysis results thusobtained correspond to the actual deposition and aggregation behavior ofthe thrombocytes, corresponding to the platelet reaction of the primaryhemostasis or the coagulation behavior of the global hemostasis. Forclinical analysis, the volumetric flow and/or the flow volume presentwhich have flowed through the reaction device after a certainpredetermined measuring time has elapsed may be determined, or, if thevolumetric flow has reached a predetermined value or is approachingzero, the elapsed time and/or the flow volume are determined (GermanPatent Application 35 41 057 A1). In addition, for clinical analysis ata predetermined flow volume, the time elapsed and/or the volumetric flowpresent at the time are evaluated as platelet parameters. Furthermore,the measured pressure change and/or the volumetric flow achieved after apredetermined time, or the elapsed time when a predetermined pressurevalue and/or a volumetric flow is reached, may be used as measurementparameters for the global, in particular the primary, hemostasis.

[0022] An additional measurement analysis is performed by providingafter a precise predetermined measurement time an insert having at leastone surface which is able to act as one or multiple boundary surfaces toform one or multiple reaction openings, it being possible to remove theinsert from the measurement system. At the particular boundary surface,which optionally may be bioactive or capable of deposition, thrombocytesmay have deposited and aggregated under the effect of shear forces orflow forces created according to a characteristic curve. Thecharacteristic curve is preferably formed in such a way that itcorresponds to a constant shear rate/shear force or flow rate. Theextent and type of the platelet reaction on the boundary surface may beoptically evaluated after fixing the platelet formation by an electronicmicroscope scanning system, for example, followed by computerized imageanalysis and display of the measurement parameters for making theclinical diagnosis. Other forms of optical evaluation may also be used(European Patent Application 0 635 720 A2).

[0023] Various embodiments may be used for the reaction device.Preferably, an embodiment is used in which the adhesion and aggregationof the blood components (thrombocytes) are induced under specified shearforce conditions. A reaction opening (aperture) such as that in knowndevices may be used for measuring the platelet function of the primaryhemostasis, for example in the form of an opening in a partition betweenthe storage chamber and the pressure gauge chamber (European PatentApplication 0 316 599 A2) or membrane (European Patent 0 138 190 B1 orEuropean Patent 0 111 942). Preferably, one or multiple reactionopenings (apertures) are used which are totally or partially enclosed bya hydrophilic material such as polystyrene, glass, or the like, or by abioactive material, in particular collagen, or which are made of thesematerials (U.S. Pat. Nos. 5,854,076 A; 5,602,037; and 5,662,107 A).

[0024] A very important factor for clinical acceptance of a method, inaddition to supplying clinically relevant data, is the economical use ofinexpensive, disposable measurement inserts and the ability to carry outthe measurements using small blood samples. Thus, in the describedreaction devices having a corresponding design, it is possible to usesmall quantities of blood for the measurement so that, under thedescribed measurement conditions, blood is conveyed from the storagechamber, through the reaction device, into the collection chamber, andback, which may result in coagulation or platelet reactions of theglobal, in particular primary, hemostasis in the reaction opening(s) andin fact until the parameter-forming measurement limits (time, volume,volumetric flow, pressure, deposition formation for the opticalevaluation, and so forth) of the particular measurement program havebeen reached, in order to then be able to provide diagnostic results, aspreviously described.

[0025] Methods for measuring the platelet reaction under shearconditions (European Patent Application 0 635 720 A2, for example) use ablood viscosity of 3000 μPa·s, for example, as the standard incalculating the shear rate. Under these conditions, all the measurementsare then carried out without evaluating the existence of significantdifferences in the viscosity in different patients. After the viscosity,as a formula component, has exerted considerable influence on themagnitude of the shear rate, in reality very divergent shear rates aremeasured compared to the predetermined rates, which leads to erroneousmeasurement results. Advantageously, in the aforementioned measuringdevices the blood viscosity can be specified in the initial phase bymeans of the precisely dimensioned geometry of the flow openings, theadjusted volumetric flow, and the resulting conveyor pressure, using acomputerized control mechanism. Hence, the correct shear rate can beadjusted automatically, and the effect of the viscosity can be largelycorrected as the measurement progresses.

EXAMPLES

[0026] The invention is described in more detail using exemplaryembodiments, with reference to the figures:

[0027]FIG. 1 shows an exemplary embodiment of a measurement system fordetecting the coagulation functions of the global, in particular theprimary, hemostasis in whole blood or platelet-rich plasma;

[0028]FIG. 2 shows an enlarged illustration of an embodiment of areaction device for detecting the coagulation functions of the global,in particular the primary, hemostasis, which may be used in theexemplary embodiment shown in FIG. 1;

[0029]FIGS. 2a through 2 e show embodiments of reaction sites which maybe used in the reaction device shown in FIGS. 2 through 6, and FIGS. 17and 19;

[0030]FIG. 3 shows a further embodiment of a reaction device fordetecting the coagulation functions of the global, in particular theprimary, hemostasis, which may be used in FIG. 1;

[0031]FIG. 4 shows a further embodiment of a reaction device which maybe used in the device according to FIG. 1, and which corresponds toFIGS. 2 and 3 with respect to applicability;

[0032]FIGS. 4a and 4 b show an embodiment of a reaction site which maybe used in the reaction devices shown in FIGS. 3 and 4;

[0033]FIG. 5 shows a further exemplary embodiment of a reaction devicewhich may be used in the device according to FIG. 1;

[0034]FIG. 6 shows a further exemplary embodiment of a reaction devicewhich may be used in the arrangement according to FIG. 1;

[0035]FIG. 7 shows an embodiment of a reaction site impression in thevessel base/intermediate base of the vessel and/or an insert for formingflow openings which can be used in the exemplary embodiments shown inFIGS. 3 and 4; 5; 6; 17; and 19;

[0036]FIG. 8 shows an embodiment of a reaction site impression in thebase/intermediate base of the vessel and/or an insert for forming flowopenings which can be used in the exemplary embodiments of FIGS. 3 and4; 5; 6; 17; and 19;

[0037]FIGS. 9a through 9 c show embodiments of flow openings in reactionsites which may be used in the devices according to FIGS. 3 and 4; 5; 6;11; 17; and 19;

[0038]FIGS. 10a through 10 c show embodiments of flow openings inreaction sites which may be used in the devices according to FIGS. 3 and4; 5; 6; 17; and 19;

[0039]FIG. 11 shows a further exemplary embodiment of a reaction devicefor detecting the coagulation functions of the global, in particular theprimary, hemostasis, which may be used in the device according to FIG.1;

[0040]FIG. 12 shows a further exemplary embodiment of a reaction devicewhich may be used in the device according to FIG. 1;

[0041]FIGS. 12a through 12 d show embodiments of reaction sites, inparticular reaction openings, which may be used in the reaction deviceaccording to FIGS. 12; 13; 16; 18; and 22;

[0042]FIGS. 13 through 24 show further exemplary embodiments ofmeasurement systems for examining blood, in particular for detecting theplatelet function of the primary hemostasis;

[0043]FIG. 25 shows graphical illustrations of measurement resultsobtained using the exemplary embodiments of the measurement systems;

[0044]FIG. 26 shows graphical illustrations of various possible shearforce/shear rate characteristic curves;

[0045]FIG. 27 shows a graphical illustration of a characteristic curvefor regulating the volumetric flow depending on the pressure rise in areaction opening, at a constant shear rate;

[0046]FIG. 28 shows measurement results for hemostasis functions; and

[0047]FIG. 29 shows measurement results for hemostasis functions.

[0048] In the device illustrated in FIG. 1, a storage chamber 15 for theblood to be examined is provided in a storage vessel 2. For the testingto detect the platelet function of the primary hemostasis and/or thefunctional properties of the global hemostasis, for example, the bloodis transported from storage chamber 15 through a reaction device 39.Reaction device 39 has a reaction site, such as a reaction opening 5 ora reaction channel, for example, for which various embodiments may beprovided. These embodiments are described in more detail below.

[0049] The particular reaction site (reaction opening) of reactiondevice 39 may be designed in such a way that blood components, inparticular thrombocytes, adhere and aggregate there, thereby partiallyor totally clogging the reaction opening. The cross section of the flowprovided in the reaction opening is thereby narrowed, resulting inincreased flow resistance. A conveyor pressure corresponding to thepressure difference between a pressure, in particular suction pressure,generated by a conveyor device, and the external pressure (atmosphericpressure) acts on the blood to be examined which is present in storagechamber 15. This conveyor pressure is altered during the cross-sectionalnarrowing of the reaction opening as a result of the possible depositionand aggregation of thrombocytes, or by a reduction in the flowability ofthe blood caused by the onset of global, in particular primary, bloodcoagulation, and thus, increased flow resistance.

[0050] In the exemplary embodiments illustrated in the figures, apiston-cylinder system 1 is used to generate the conveyor pressure whichacts in a working chamber 12 on one side of reaction device 39. Thissystem comprises a cylinder 25 (measuring cylinder) in which a piston 4is displaceably guided in the axial direction. A motor 17 is provided asthe piston drive, which may be designed as a stepping motor. Motor 17may be connected to piston 4 via a coupling 13. Coupling 13 isdetachable, so that piston-cylinder system 1 can be separated from motor17. In the exemplary embodiment illustrated, a pressure gauge chamber 3is situated below storage chamber 15. Pressure gauge chamber 3 islocated inside a pressure-sealed space into which the blood to beexamined enters after passing through reaction device 39. In theexemplary embodiment illustrated, this pressure-sealed space is situatedin working chamber 12 of piston-cylinder system 1. The blood which haspassed through reaction opening 5 and central flow opening 11 ofreaction device 39 collects on a working surface 33, which in theexemplary embodiments illustrated in FIGS. 1 through 17 is directedupward. Piston 4 is sealed with respect to the inner wall of cylinder 25in such a way that the quantity of blood being collected can be used asa measured variable for the flow volume. A liquid meniscus which formson the cylinder wall creates an additional gas-tight seal. Cylinder 25may therefore be used at the same time as a measuring cylinder, sincethe movement of piston 4 by means of drive 17 may be regulated bycontrol unit 18, thus enabling the volumetric flow and the flow volumethrough the reaction opening to be accurately detected as a measuredvariable.

[0051] Pressure gauge chamber 3 is situated above the surface of theblood present in cylinder 25 which has passed through reaction device39. Pressure gauge chamber 3 is free of the blood to be examined. Apressure line 8 designed as a hollow needle projects into pressure gaugechamber 3. Hollow needle 8 may have a tip, which is pushed through theplastic material of cylinder 25. To this end, a lifting magnet 19 may beused to push hollow needle 8 through the wall of cylinder 25. Thisensures a pressure-sealed penetration of hollow needle 8 through thecylinder wall. A pressure gauge (pressure sensor) 9 is connected to thehollow needle or pressure line 8. Pressure line 8 may also be joined ina pressure-sealed manner to pressure chamber 8 in other ways, via aconnector, for example. Pressure gauge 9 generates measurement signalswhich correspond to the pressure in pressure gauge chamber 3. Instead ofthe arrangement illustrated for detecting and measuring the pressure, apressure sensor may be installed in pressure gauge chamber 3 whichgenerates corresponding signals which may be relayed wirelessly or viaelectrical connecting wires. Pressure gauge 9 is connected to a controlunit 18. Control unit 18 controls the drive of motor 17, and thus thedrive of piston 4, depending on the measured pressure in pressure gaugechamber 3. During the entire measuring process, piston 4 may optionallybe moved in only one direction by the motor drive, specifically, fromthe upper position shown in FIG. 1 to a lower position. However, it isalso possible, up to the end of a measurement, to effect a pulsatingback and forth motion of the piston under predetermined measurementconditions, using motor 17 which is regulated by control unit 18. Inthis manner the blood is pulsatingly moved back and forth throughreaction device 39 under predetermined shear conditions in the reactionopening(s) or shear opening(s). Hollow needle 8 may also be connected tobleeder valve 20, making it possible to optionally alter air pocket 62in pressure gauge chamber 3 by the movement of piston 4.

[0052] Using a stop 68, it is possible to bring piston 4, which with itsworking surface 33 forms the lower boundary of a pressure-sealed bloodcollection chamber 10 for collecting the blood which has passed throughreaction device 39, into a reference position by moving working surface33 against this stop before the measurement is begun. As shown by theexemplary embodiments illustrated in FIGS. 2 through 12, storage vessel2 and cylinder 25 are preferably constructed as one piece.

[0053] Storage vessel 2 and cylinder 25 may be enclosed by a heatingsleeve 23 whose temperature can be regulated.

[0054] The figures illustrate various exemplary embodiments of themeasurement system, and in particular, various embodiments of reactiondevices 39 which may be used in the measurement system shown in FIG. 1.

[0055] In the exemplary embodiments illustrated in FIGS. 2 through 4,reaction openings 5 are designed in such a way that deposition of theblood components, in particular thrombocytes, is initiated on theboundary surface 29 of insert 14 by the action of regulated shearforces. After the measurement process has ended, insert 14 may beremoved from storage vessel 2 and the deposited platelet formation 28examined by optical, electron microscope, chemical, or physical meanswhile forming clinical diagnostic measurement parameters.

[0056] In the exemplary embodiment shown in FIG. 2, reaction device 39has a reaction site or reaction opening 5 which is formed by twooppositely facing boundary surfaces 29 and 30. Boundary surface 29,which preferably has a flat design, is situated on an insert 14 in theform of a plunger. Boundary surface 30 is situated on vessel base 31 ofstorage vessel 2. The two boundary surfaces 29 and 30 may run parallelor nonparallel with respect to one another, the increase in the distancebetween the outside and the inside being negligible. The distancebetween the two boundary surfaces 29 and 30 defines the height ofreaction opening 5. In the exemplary embodiment illustrated, thisreaction opening extends essentially horizontally, that is,perpendicular to the direction of motion of piston 4. The conveyorpressure in working chamber 12 generated by piston-cylinder system 1situated underneath acts via a central opening 11 and reaction opening 5in storage chamber 15 of storage vessel 2. Central opening 11 may alsobe formed by the interior of a tube 16 which can be inserted intocentral flow opening 11. Central flow opening 11 or tube 16 may be usedas the feed opening and/or the shear opening. The blood is transportedfrom the outer edge of reaction opening 5 to central flow opening 11 ortube 16. In reaction opening 5, shear forces act on the bloodcomponents, thereby enabling the thrombocytes to deposit and aggregatepreferably on the underside of insert 14, that is, on boundary surface29. Or, this may result in a change in the flowability of the bloodduring blood coagulation (clot formation) of the global, in particularthe primary, hemostasis, especially by back and forth pumping of theblood through the reaction opening. Since boundary surface 30 hashydrophobic properties, platelet reaction cannot occur there.

[0057] Plunger-shaped insert 14 is properly positioned in the storagevessel by means of locking and spacing bars 24. The gap height ofreaction opening 5 is fixed by the spacer function. Boundary surface 29is designed as a reaction surface on the underside of insert 14, whichoptionally is removable from the measurement system by means of agripping arrangement (not shown in greater detail). For this purpose,this boundary surface may be appropriately coated or designed, as shownin FIGS. 2c through 2 e. For example, underside 32 of insert 14, whichforms boundary surface 29, or the entire insert 14 may be made of ahydrophilic material, such as polystyrene or glass, on which plateletscan adhere. For certain applications, underside 32 may be kepthydrophobic and/or be provided with a roughness sample. On lower surface32 of insert 14 it is also possible to provide, as shown in FIG. 2d, abioactive coating 35 in the form of an extracellular matrix (ECM),thrombin, batroxobin, collagen (also natural recombinant collagen orpurified collagen subtypes), synthetic peptides containing collagen-likeamino acid sequences, laminin, thrombospondin, fibronectin, blood cells,in particular erythrocytes or leucocytes, preferably of blood type O orcontaining von Willebrand factor, or a mixture of collagen (as above) orsynthetic peptides, respectively, with substances such as adenosinediphosphate (ADP), adrenalin, thrombospondin, or fibronectin, or otherbioactive substances as described in U.S. Pat. Nos. 5,854,076A or5,662,107A, for example, in order to form such a bioactive boundarysurface 29 for reaction opening 5. In addition, boundary surface 29 maybe designed in such a way that the surface of the insert is totally orpartially covered with a nonporous coating 48 and/or a porous coating 49in the form of a film or membrane (cellulose acetate), as shown in FIG.2e. This coating may be covered or impregnated with the bioactivesubstances listed above. The bioactive film or membrane may also be madeof collagen. As indicated in FIG. 2e, the coating may have a varieddesign. A plurality of measurement results may then be simultaneouslyobtained, if desired. The varied covering/coating may be produced insections or in halves. FIG. 2a shows boundary surface 29 with depositedthrombocytes after a measurement has been carried out. FIG. 2b showsvessel base 31 in a top view for clarification.

[0058] In FIGS. 3 and 4, the blood flowability may be altered duringblood coagulation (global hemostasis) in the same manner as for FIG. 2;otherwise, the platelet reaction of the primary hemostasis shouldlikewise preferably take place on boundary surface 29 of insert 14, asshown in FIG. 2, and both (29 and 14) may be designed according to thedescription for FIG. 2 (material and bioactive covering/coating). Insert14 is likewise removable. The design shown in FIG. 4 differs from thatin FIG. 3 solely by the fact that insert 14 along with surface 32, whichforms boundary surface 29, has the shape of a flattened cone, and vesselbase 31 has been adapted to the shape of support surface 51.

[0059] In the embodiments illustrated in FIGS. 3 and 4, cross-shapedimpressions 53 are molded into vessel base 31 (FIG. 4b). Theseimpressions 53 form indentations between support surfaces 51 on whichinsert 14, along with surface 32 forming boundary surface(s) 29 ofreaction opening(s), rests with a friction fit. This results in reactionopenings 5 which are arranged in a cross shape extending essentiallyradially and horizontally (FIG. 3), as well as inclined reactionopenings 5 (exemplary embodiment shown in FIG. 4). This results incross-shaped deposits 28 of thrombocytes on boundary surfaces 29, whichmay be formed by surface 32 of insert 14, as shown in FIG. 4a. Thesurfaces of vessel base 31, intermediate base 50, and all surfaces whichare created there by impressions 53, 52 may optionally have ahydrophobic design to avoid undesired platelet deposits.

[0060]FIGS. 5 and 6, 17, and 19 show further exemplary embodiments ofreaction devices 39 in which flow openings 21 are created by joining aninsert 14 and its surface 32 to support surface 51 of vessel base 31 orintermediate base 50 and its support surface 54. These flow openings mayform reaction openings 5 or feed openings 27 and shear openings 46.

[0061] Impressions 53 are preferably molded in vessel base 31 orintermediate base 50, as illustrated in FIGS. 4b, 7, and 8, for example.These impressions 53 form support surface 51 on which insert 14 isjoined to its surface 32 with a friction fit. This surface 32 representsa boundary surface 29 of impression 53, by which a flow opening 21 couldbe formed, as shown in FIG. 10a. In this arrangement, surface 32 ofinsert 14 may also be designed in such a way that the surface representsa boundary surface 29, as described for FIGS. 2c through 2 e, whichalong with impression 53 creates a flow opening which acts as a reactionopening 5 in which thrombocytes may optionally deposit and agglomerate.

[0062] In a similar manner as above, flow opening 21 may also bedesigned in such a way that an impression 52 is present only in insert14, and the impression creates a support surface 32 there which isjoined with a friction fit to support surface 51 of vessel base 31, orto support surface 54 of intermediate base 50, thereby forming aboundary surface 30 or 54, respectively, to form a flow opening 21 forimpression 52 as shown in FIG. 10b. The boundary surfaces of flowopening 21 may then be designed according to FIGS. 9a, 9 b, and 9 c andtheir descriptions. In addition, impressions 52 may be freely chosenwith respect to their number and shape, and may also correspond to thosein intermediate base 31, according to FIGS. 4b, 7 and 8.

[0063] Furthermore, similar to the description above, mirror-imageimpressions 52 may be situated in insert 14 and impressions 53 may besituated in vessel base 31 or intermediate base 50, which then formmutual support surfaces 32 and 51 or 54, respectively. These mutualsupport surfaces are joined to one another with a friction fit so thatimpressions 52 and 53 overlap precisely to form a flow opening 21, asshown in FIG. 10c,-for example. The boundary surfaces of flow opening 21may then be designed according to FIGS. 9a, 9 b, and 9 c and theirdescriptions.

[0064] The cross sections of flow openings 21 in FIGS. 10a through 10 care shown as examples, and may have different shapes or may be exchangedwith one another. On the other hand, the number, type, and shape of flowopenings 21 may be differently chosen, as shown in FIGS. 4b, 7, 8, and 9a through 9 c, depending on the requirements.

[0065] Flow openings 21, whose design has been described for thereaction devices shown in FIGS. 5 and 6, 17, and 19, may performdifferent functions as a result of the respective surfacestructure/coating created. In FIG. 9a, the section of a flow opening 21shown is a feed opening 27, for example, and at the same, if desired, isa shear opening 46 when boundary surfaces 6 of opening 21 acthydrophobically. If, on the other hand, boundary surface 6 is kepthydrophilic, a reaction opening 5 is formed in which platelets mayreact. FIG. 9b shows that in flow opening 21 a predetermined area ofboundary surface 6 is provided with a bioactive coating 35, therebyforming a reaction opening 5. The upstream and downstream areasrepresent boundary surfaces 6 which are kept hydrophobic and whichtherefore can simultaneously form feed openings 27 and shear openings46. FIG. 9c shows a flow opening 21 whose boundary surface 6 hasreceived a bioactive coating 35 along its entire length, thereby forminga reaction opening 5 on which platelets can react under the action ofshear forces. Feed openings 27 and shear openings 46 may have adifferent cross section, similarly as for reaction opening 5, in theexemplary embodiments shown in the aforementioned figures. Bioactivecoating 35 may be made of collagen (also natural recombinant collagen),synthetic peptides having collagen-like amino acid sequences, purifiedcollagen subtypes, laminin, fibronectin, thrombospondin, and othererythrocytes, or may be made of a mixture of collagen (as above) orsynthetic peptides with adenosine diphosphate (ADP), adrenalin,fibronectin, thrombospondin, or other substances which activate theplatelets (U.S. Pat. Nos. 5,854,067A and 5,662,107A).

[0066] In the exemplary embodiments shown in FIGS. 2 through 6, 17, and19, insert 14 and vessel base 31 are made predominantly of plastic. Thecross section of insert 14 which forms surface 32, in addition to theshapes shown in FIGS. 2 through 4, may also have an arc-shaped or adownwardly tapering design, and vessel base 31 together with itsboundary surface 30 or support surface 51 are then adapted to theseshapes. Insert 14, as seen from above, may have a round shape, or also atriangular, oval, square, or polygonal shape, as may the receivingdevice in vessel base 31 in a corresponding manner. An insert receptaclemay be molded on vessel base 31 and/or on the vessel wall of storagevessel 2 in the form of locking and spacing bars 24 into which insert 14is introduced.

[0067] The embodiment shown in FIG. 5 corresponds for the most part tothe embodiment arrangement shown in FIG. 3, except that in FIG. 5,insert 14 cannot be removed from the storage vessel. The embodimentpossibilities of reaction device 39 correspond to FIGS. 4a and 4 b, 7and 8, 9 a, b, and c, 10 a, b, and c, and their previous descriptions. Atube 16 or hollow needle 55 made of steel, plastic, or glass may beinserted into central opening 11, the flow surfaces of the tube orhollow needle having a hydrophobic design so that shear effects(pre-shearing) can be created without producing platelet depositionthere. In reaction openings 5 and 7 in reaction device 39, the action ofthese pre-shear forces results in platelet deposition. This is true forall the embodiments shown in FIGS. 2 through 24.

[0068] In the embodiment illustrated in FIG. 6, intermediate base 50 isformed on an extension of vessel base 31. Intermediate base 50 includescentral opening 11 through which the blood to be examined is led fromstorage chamber 15 into reaction device 39. The blood flows from centralopening 11, outwardly from the center to the edge of the reactiondevice. The embodiment possibilities of reaction device 39 likewisecorrespond to FIGS. 4a and 4 b, 7 and 8, 9 a, b, and c, 10 a, b, and c,and their previous descriptions. A tube 16 may be inserted into centralopening 11 of intermediate base 50, in which pre-shearing of the bloodoptionally takes place, corresponding to the description for FIG. 5. Thesame reaction device 39 is provided in FIG. 19.

[0069] The illustrated exemplary embodiments of the measurement systemmay have the following dimensions. The diameter and the height ofstorage vessel 2 may be approximately 10 to 20 mm. The height ofmeasuring cylinder 25 may be approximately 20 to 50 mm. The diameter ofmeasuring cylinder 25 may be approximately 8 to 15 mm. Flow opening 21in central flow opening 11 may have a diameter of approximately 0.300 to3 mm, and for tube 16, a diameter of approximately 0.100 to 2 mm. Thelength of central flow opening 11 and of tube 16 may each be 0 toapproximately 35 mm. The volume present in pressure gauge chamber 3 maybe approximately 10 to 50 μL, although in FIGS. 18 through 24 the volumeis approximately 500 to 1000 μL.

[0070] In the exemplary embodiment illustrated in FIG. 11, tube 16 issituated in an extension which is integrally molded on vessel base 31.The tube may be made of plastic, glass, or steel. Flow opening 21 oftube 16 may be designed as a reaction opening 5 and lined with abioactive coating 35 according to the description for FIG. 9c.Corresponding to FIG. 9b and its description, however, flow opening 21may also be divided into a dimensioned section which forms reactionopening 5, and one or two remaining sectional portions which may formfeed openings 27 or shear openings 46. The region representing reactionopening 5 may also be situated at the inlet, in the center, or at theoutlet of tube 16.

[0071] The tube preferably is made of polystyrene or glass, boundarysurface 6 of flow opening 21 then having a hydrophilic design (in whichcase the bioactive coating may be omitted), thereby forming reactionopening 5 according to FIG. 9a and its description. The diameter of flowopening 21 of tube 16 may be approximately 0.15 to 2 mm. The length maybe approximately 10 to 30 mm. Optionally, tube 16 may be arranged in theextension so as to be removable, so that evaluation is possible outsidethe measurement system after the measurement has been completed. In theexemplary embodiment illustrated, piston 4 is cup-shaped on its upperend and encloses the downwardly directed extension, integrally molded onvessel base 31, in which tube 16 is situated. In this manner thesmallest possible air pocket 62 can be formed in pressure gauge chamber3.

[0072] In the embodiment shown in FIG. 12, a reaction opening 7 isprovided on the lower end of tube 16 which runs in an extension of thevessel base. Flow opening 21 of tube 16 may act as a feed opening 27and/or a shear opening 46. Reaction opening 7 may be designed in amanner known from European Patent 0 111 942 or European PatentApplication 0 316 599 A1. Reaction opening 7 or partition 34 arepreferably designed as illustrated in FIGS. 12a through 12 d. In theembodiment shown in FIG. 12a, reaction opening 7 is situated in apartition 34 which is made of plastic, for example polystyrene, havinghydrophilic surfaces, or which is made of a bioactive material, capableof depositing platelets, in the form of a bioactive film or a nonporouscollagen membrane, for example. In the embodiment shown in FIG. 12b,partition 34 is made of a nonporous material provided with a bioactivecoating 35, as described below, on one or both partition surfaces, or onboth partition surfaces and/or on boundary surface 6 of reaction opening7. In the embodiment illustrated, both partition surfaces of partition34 and the boundary surface of the opening are provided with a bioactivecoating 35. Bioactive coating 35/impregnation may be made of collagen(also natural recombinant collagen or purified collagen subtypes),synthetic peptides having collagen-like amino acid sequences, laminin,fibronectin, thrombospondin, or other substances, or bioactivesubstances (U.S. Pat. Nos. 5,854,076A or 5,662,107A) to which plateletsadhere, or a mixture of collagen (as above) or synthetic peptides withadenosine diphosphate (ADP), adrenalin, fibronectin, laminin,thrombospondin, or other substances which activate the platelets. In theembodiments shown in FIGS. 12c and 12 d with reaction opening 7, it isadvantageous to coat one or both partition surfaces of nonporouspartition 34 with a porous layer 70 or membrane (sandwich) made ofcellulose acetate, for example, with corresponding coating/impregnationas described in FIG. 12b for nonporous partition 34. However, it is alsopossible to use only a porous material as partition 34 which is coatedor impregnated in the same manner as for the aforementioned nonporousmaterial shown in FIG. 12b (U.S. Pat. No. 5,854,076).

[0073] In the exemplary embodiment illustrated in FIG. 12, reactionopening 7 is situated at the lower end of tube 16, which may have alength of 0 to approximately 35 mm and a diameter of approximately 0.150to 2 mm. Partition 34 having reaction opening 7 may also be providedapproximately in the center of tube 16, in the direction of thelongitudinal axis of the tube (not shown). In the absence of tube 16,partition 34 having reaction opening 7 may also be installed in a recessin vessel base 31. The diameter of the opening of reaction opening 7 maybe approximately 0.100 to 0.500 mm. The wall thickness of the partitionmay be approximately 0.10 to 6 mm.

[0074] In the exemplary embodiment illustrated in FIG. 13, the storagechamber is situated in cylinder 59, preferably in a blood withdrawalsyringe. Reaction device 39 is essentially designed as illustrated inFIG. 12, but may also have a design as illustrated and described forFIGS. 6 and 11. The blood to be examined which is present in storagechamber 15 of syringe cylinder 59 of withdrawal syringe 45 flows througha hollow needle 55 which is attached in a pressure-sealed manner inhousing 64 and which with its upwardly pointing free needle end 47 isinserted through a sealing insert in syringe adapter 22 of syringecylinder 59, through reaction device 39, and into blood collectionchamber 10 situated underneath. To this end, as already described,piston 4 is moved downward along measuring cylinder 25 to carry out themeasurement. Also in this embodiment, piston 4 in measuring cylinder 25may optionally move the blood back and forth in reaction device 39 underthe measurement conditions. Hollow needle 55 has a totally hydrophobicdesign on the surface, and may be made of steel, plastic, or glass. Itsflow opening may act as a feed opening 27 and as a shear opening 46.This embodiment of hollow needle 55 may be used in the same way as shownin FIGS. 14 and 15, and 22 through 24.

[0075] Reaction opening 7 is preferably designed as described in FIGS.12a and 12 b. The pressure is measured in pressure gauge chamber 3 viapressure line 8, as explained in the previously described exemplaryembodiments. Hollow needle 55 is firmly attached to a housing 64 inwhich reaction device 39 is accommodated. Ventilation/bleeding 61 isprovided for an air pocket 62 situated above the blood sample present instorage chamber 15 so that no back pressure can develop in this spaceduring the measurement movement of piston 4 in piston-cylinder system 1.

[0076] In the exemplary embodiment illustrated in FIG. 14, hollow needle55 is likewise attached to housing 64 of reaction device 39. Reactiondevice 39 may also be designed in the same manner as for the exemplaryembodiments shown in FIGS. 6 and 11 through 13. Hollow needle 55 isprovided with a catheter 57 via a sealing collar 56 for the directmeasurement of the patient's blood from the vein, for example.

[0077] In the exemplary embodiment illustrated in FIG. 15, storagechamber 15 for the blood to be examined is situated in a container 65which may be mounted on hollow needle 55 which is fastened to housing64. The tip of free needle end 47 is pushed into storage chamber 15 inthe base region of container 65. The penetrated material in the baseregion of container 65 makes sealing contact with hollow needle 55, sothat when piston 4 is moved the desired transport of the blood to beexamined takes place through reaction device 39. In contrast to FIG. 13,this embodiment is suitable for measuring pipetted blood to whichsubstances have been added, for example, or which has been otherwisemanipulated, or for measuring when only a small quantity of blood (lessthan 500 μL, for example) is available for a control measurement. Inthis exemplary embodiment, reaction device 39 may likewise be designedas illustrated in FIGS. 6 and 11 through 14.

[0078] In the exemplary embodiment illustrated in FIG. 16, thepiston-cylinder system of a specialized syringe (not shown) or awithdrawal syringe (disposable part) acts as a conveyor device totransport the blood to be examined from working chamber 12 of theconveyor device, which here is used as a storage chamber 15, via hollowneedle 55 which is fastened in a pressure-sealed manner in central flowopening 11, and then through reaction device 39. In this arrangement,the upper vessel includes blood collection chamber 10. For this purpose,piston 4 present in syringe cylinder 59 is connected to drive 17 via acoupling, not illustrated in further detail. Using electric drive device17 according to the measurement program regulated by control unit 18,piston 4 in syringe cylinder 59 may be moved upward in one direction forconveying the blood through reaction device 39. Piston 4 may also bemoved back and forth so that the blood present in partition 34 flowsthrough reaction opening 7 from alternating directions. The reactionopening may be designed according to FIGS. 12a and 12 b and thedescription for FIG. 12. Partition 34 may be situated in a recess invessel base 31 of upper vessel 2.

[0079] In the exemplary embodiment illustrated in FIG. 16, reactiondevices 39 may also be used which correspond to the exemplaryembodiments shown in FIGS. 2 through 5, 11, and 17 and the accompanyingdescriptions.

[0080] In order to connect reaction device 39 to the withdrawal syringe,whose working chamber 12 in this particular embodiment is at the sametime storage chamber 15 and is filled with anticoagulated bloodwithdrawn from patients for carrying out the measurement process, thedownwardly projecting free needle end 47 of hollow needle 55 is guidedin a pressure-sealed manner through sealing insert 26 into a syringeadapter. The interior of syringe adapter 22 of withdrawal syringe 45forms pressure chamber 3. The other end of hollow needle 55 is firmlyconnected to vessel base 31 in central flow opening 11. As alreadymentioned, withdrawal syringe 45 forms piston-cylinder system 1 whosepiston 4 is connected to drive 17 via a coupling 13, not shown. Piston 4is preferably moved upward in cylinder 25 in the direction towardreaction device 39, pushing the blood column formed by the inner wall ofcylinder 25 upward with its working surface, with bleeder valve 20 open,until the upper blood level is detected at a precisely defined positionby a level sensor 58 which then signals the reference position tocontrol unit 18, whereupon the measurement can begin. The referenceposition defines the volume of air pocket 62 which forms blood-freepressure gauge chamber 3 and which is bounded by the outside of hollowneedle 55, the blood level, the inner wall of syringe adapter 22, andthe underside of sealing insert 26.

[0081]FIG. 17 shows an embodiment having a reaction part 39 which maycorrespond to those shown in FIGS. 2 through 5. Otherwise, theembodiment is identical to that described in FIG. 16.

[0082] In the exemplary embodiments illustrated in FIGS. 18 through 24,a conveyor device 36 for generating the conveyor pressure is situatedoutside common housing 38. The conveyor device comprises apiston-cylinder system having a cylinder 40 and piston 4. As describedfor the aforementioned exemplary embodiments, piston 4 is driven by anelectrical drive device such as a stepping motor 17. Pressure line 8,which may be designed as a hollow needle, and whose tip is pushedthrough container wall 37 of blood collection chamber 10 by means of adrive 19 according to the description for FIG. 1, conducts the conveyorpressure generated in working chamber 12 of the piston-cylinder system.This pressure corresponds to the pressure to be measured in pressuregauge chamber 3. To this end, a pressure gauge line 41 is branched offfrom pressure line 8 and connected to pressure gauge line 9. In a mannersimilar to the exemplary embodiments already described, pressure gauge 9(sensor) is connected to control unit 18 to which electrical drive unit17 is joined. Blood collection chamber 10 is situated in common housing38 below storage vessel 2. Reaction device 39 may be designed as shownin the exemplary embodiments illustrated in FIGS. 12 through 15. Anotherpossibility is that reaction device 39, which is preferably designed asa separate insert, is inserted in common housing 38 of storage vessel 2and in blood collection vessel 66 in such a way that it comes to rest onboundary bars 44. For this purpose, the outer ring of the portion ofreaction device 39 which forms vessel base 31 is designed in such a waythat the ring is able to act as a sealing element 66 for the inner wallof storage vessel 2. This embodiment may also optionally be used withother embodiments. A blood sensor 67 is situated in blood collectionchamber 10 below reaction device 39. This sensor determines the firstdrops of blood passing through reaction device 39, and a converter 63then sends a signal to control unit 18 indicating readiness to start themeasurement.

[0083] However, the embodiments already described in FIGS. 2 through 17may also be used for reaction devices 39.

[0084] A reaction device 39 is used in FIG. 19 as described in theexemplary embodiment shown in FIGS. 3 and 5.

[0085] A reaction device is used in FIG. 20 as described in theexemplary embodiment shown in FIGS. 3 and 5.

[0086] In the exemplary embodiment illustrated in FIG. 21, storagechamber 15 for the blood to be examined is situated in the cylinder of awithdrawal syringe 45 in a manner similar to the exemplary embodimentshown in FIGS. 13 and 22. Reaction device 39 is situated in housing 64which, as shown in FIG. 18, has pressure-sealed blood collection chamber10 in its lower portion. Piston-cylinder system 36, by which themeasurement pressure is built up and which is used to convey the bloodthrough reaction device 39, may be designed as illustrated in FIG. 18.

[0087] A hollow needle 43 connected to withdrawal syringe 45 via cannulaadapter 60 may be pushed through a region of the wall of housing 64, asshown in FIG. 21. A pressure-sealed connection is established withreaction device 39 inside the housing. The measurement process forexamining the blood, the combination with reaction devices 39 shown inthe other figures, and the design of parts are achieved as explained forthe aforementioned exemplary embodiments, particularly as in FIG. 13.Ventilation/bleeding 61 is provided for an air pocket 62 situated abovethe blood sample present in storage chamber 15, so that no back pressurecan develop in this space during the measurement movement of piston 4 inpiston-cylinder system 36.

[0088] Instead of the conveyor device in the form of piston-cylindersystem 36 as shown in FIG. 18, a piston-cylinder system 1 may be usedwhich is integrated into housing 64, as used in the exemplaryembodiments of FIGS. 1 through 17. The possible reaction devices 39 mayalso be used as described and designated for FIGS. 13 and 22.

[0089] The exemplary embodiment illustrated in FIG. 22 is employed byusing the external conveyor device in the form of a piston-cylindersystem 36 corresponding to FIG. 18. Blood collection chamber 10 issituated in a container sealed at the bottom, also as in FIG. 18.Otherwise, this design is essentially identical to that shown in FIG. 13and its description.

[0090] The measurement system illustrated in FIG. 23 correspondsessentially to that shown in FIG. 14, and the measurement system shownin FIG. 24 corresponds essentially to the measurement system illustratedin FIG. 15, except that the measurement system is applied according toFIG. 18 and according to the description for FIG. 22. In contrast toFIG. 22, the embodiment shown in FIG. 24 is also suited for measuringpipetted blood to which substances have been added, for example, orwhich has been otherwise manipulated, or for measuring when only a smallquantity of blood (less than 500 μL, for example) is available for acontrol measurement.

[0091] Using the exemplary embodiments explained in FIGS. 3 through 24,the detection of the platelet function of the primary hemostasis mayalso be carried out in such a way that the measured pressure ismaintained at a desired value by back-coupling, and the quantity ofblood flow through the capillary is determined as a measure of theaggregation or coagulation of the thrombocytes (German PatentApplication 35 41 057 A1).

[0092] In addition, in the exemplary embodiments shown in FIGS. 3through 24 it is possible to carry out the detection procedure in such away that the change in pressure which occurs during the continuedaddition of the particular flow path into reaction device 39 is measuredat specified time intervals, and that the volumetric flow in each caseis altered so that it corresponds to a predetermined function.

[0093] The pressure may also be held constant during the predeterminedtime intervals, and later, when the volumetric flow has fallen by acertain amount, the pressure may be readjusted until it corresponds tothe predetermined function (German Patent Application 196 17 407 A1)

[0094] A novel method according to the invention is preferably used inwhich, depending on the pressure measured in pressure gauge chamber 3,the volumetric flow of the blood to be examined is adjusted by reactiondevice 39 in such a way that a predetermined shear rate or shear forcecharacteristic curve is achieved, and the shear rate or the shear forceis preferably held constant.

[0095] For clinical analysis, the flow volume and/or the volumetric flowpresent at the time may be used after a predetermined measuring time haselapsed, or, at a predetermined flow volume the elapsed time and/or thevolumetric flow present at the time may be used, or, at a predeterminedflow volume the elapsed time and/or the flow volume present at the timemay be used. Similarly, the pressure rise after a predetermined time, orthe elapsed time after specifying a pressure rise for the parameterformation, may be used.

[0096] The volumetric flow is adjusted according to the followingrelationship:

[0097] Volume stream$V^{\prime} = \frac{2\quad \gamma^{4}l^{3}\eta^{3}\pi}{\Delta \quad p^{3}}$

[0098] where the terms have the following meanings:

[0099] V′ is the volumetric flow of the blood to be examined which flowsthrough the reaction device, in particular through the shear opening;

[0100] Δp is the pressure measured in the pressure gauge chamber;

[0101] l is the length of the flow path in the aperture, in particularin the shear opening;

[0102] η is the viscosity of the blood to be examined;

[0103] π is 3.14; and

[0104] γ is the shear rate.

[0105] Control of the measurement system, in particular of the pistonmovement, may be carried out in such a way that the blood flow proceedsalong a predetermined characteristic curve for the shear rate or shearforce.

[0106] In FIG. 26 a nonlinearly rising shear force characteristic curveis illustrated by a dashed/dotted line, and a linearly fallingcharacteristic curve is illustrated by a dashed line. The shape of theparticular characteristic curve for the shear rate (l/s) or for theshear force (N/m²) may optionally be selected depending on the diagnosisbeing made for which the measurement is carried out. It is preferred toselect a constant characteristic curve (solid line in FIG. 26) for aspecified shear rate or shear force. For rising flow pressure resultingfrom deposition or aggregation of thrombocytes in the reaction opening,for example, the desired characteristic curve is obtained by controllingthe piston movement according to the above-referenced formula.

[0107]FIG. 25 shows parameter-forming quantities, where dashed/dottedline 1 represents the time limitation for the volumetric flow,represented by dashed line 3, and for the flow volume, represented bysolid line 4, whose values, determined by the time limitation, formmeasurement parameters. Or, if dashed line 3 representing the volumetricflow approaches zero, the measurement time indicated by line 2 isobtained as the measurement parameter, and as soon as its predeterminedvalue is reached, the value for the flow volume represented by solidline 4, or alternatively, the value of the flow volume represented bysolid line 4, forms the time represented by dashed/dotted line 1. Theseparameters are formed by the coagulation reaction of the global, inparticular the primary, hemostasis, which among other reactions arisedue to the effect of a shear quantity from a predeterminedcharacteristic curve. The shear quantity follows a predeterminedcharacteristic curve. These described parameters may be formed in theexemplary embodiments shown in FIGS. 2 through 24.

[0108]FIG. 27 shows the volumetric flow normalized to 1 at 5 mbar as afunction of the pressure difference dp for regulation of the volumetricflow, depending on dp in the reaction opening, while a constant shearrate is specified.

[0109]FIGS. 28 and 29 show measurement results, including the pressurecurve, during examination of the coagulation function of the global, inparticular the primary, hemostasis, when the volumetric flow isregulated depending on the change in pressure in the reaction opening,while a constant shear rate is specified according to FIG. 27. Thesealing time and the sealing volume are measurement values for clinicalanalysis. In FIG. 28, the volumetric flow passes through in 196 seconds,and a flow volume goes from 310.9 μL to zero.

[0110] In FIG. 29, there is hardly any deposition of platelets in thereaction opening due to the platelet-inhibiting effect of ASA(acetylsalicylic acid). The measurement limits are not reached becauseof the pharmacological effect on the platelet function.

LIST OF REFERENCE NUMBERS

[0111]1 Piston-cylinder system

[0112]2 Storage vessel

[0113]3 Pressure gauge chamber

[0114]4 Piston

[0115]5 Reaction opening

[0116]6 Boundary surface (opening)

[0117]7 Reaction opening (aperture)

[0118]8 Pressure line (hollow needle)

[0119]9 Pressure gauge (pressure sensor)

[0120]10 Blood collection chamber

[0121]11 Central flow opening

[0122]12 Working chamber of conveyor device

[0123]13 Coupling

[0124]14 Insert

[0125]15 Storage chamber

[0126]16 Tube

[0127]17 Electrical drive device (Electric motor)

[0128]18 Control unit

[0129]19 Lifting magnet

[0130]20 Bleeder valve

[0131]21 Flow opening

[0132]22 Syringe adapter

[0133]23 Heating sleeve

[0134]24 Locking and spacing bar

[0135]25 Cylinder (measuring cylinder)

[0136]26 Sealing insert

[0137]27 Feed opening

[0138]28 Thrombocyte deposition

[0139]29 Boundary surface on insert

[0140]30 Boundary surface on vessel base

[0141]31 Vessel base

[0142]32 Surface on insert

[0143]33 Working surface

[0144]34 Partition

[0145]35 Bioactive coating

[0146]36 Piston-cylinder system

[0147]37 Container wall

[0148]38 Common housing

[0149]39 Reaction device

[0150]40 Cylinder

[0151]41 Pressure gauge line

[0152]42 Needle end

[0153]43 Hollow needle (cannula)

[0154]44 Boundary bars

[0155]45 Withdrawal syringe

[0156]46 Shear opening

[0157]47 Free needle end

[0158]48 Nonporous coating

[0159]49 Porous coating

[0160]50 Intermediate base

[0161]51 Support surface (vessel base)

[0162]52 Impression (in insert)

[0163]53 Impression (in vessel base)

[0164]54 Support surface (intermediate base)

[0165]55 Hollow needle

[0166]56 Sealing collar

[0167]57 Catheter

[0168]58 Level sensor

[0169]59 Syringe cylinder

[0170]60 Cannula adapter

[0171]61 Ventilation/bleeding

[0172]62 Air pocket

[0173]63 Converter

[0174]64 Housing

[0175]65 Container

[0176]66 Sealing element

[0177]67 Blood sensor

[0178]68 Stop bar

[0179]69 Sealing wall (housing 64)

[0180]70 Porous layer

Key for Figures

[0181]FIG. 25

[0182] Volumenfluβ=Volumetric flow

[0183] Volume=Volume

[0184] Zeit=Time

[0185]FIG. 26

[0186] Scherrate=Shear rate

[0187] Scherkraft=Shear force

[0188] Druck=Pressure

[0189]FIG. 27

[0190] Caption: Regulation of the volumetric flow depending on dp in thereaction opening (sealing zone), at a specified constant shear rate

[0191] Volumenfluβ V′ normiert auf 1 bei 5 mbar=Volumetric flowV′normalized to 1 at 5 mbar

[0192] Druckunterschied=Pressure difference

[0193]FIG. 28

[0194] [Text is illegible]

[0195]FIG. 29

[0196] [Text is illegible]

1. Device for examining the properties of the global, in particular the primary, hemostasis functions in whole blood or platelet-rich plasma, comprising a storage chamber (15) for the blood to be examined, a reaction device (39) having at least one flow path (5, 7, 11, 16) via which blood to be examined is transported for carrying out certain reactions, a conveyor device (1) which conveys a volumetric flow for the transport of the blood through the reaction device (39), thereby generating a conveyor pressure, a pressure gauge (8, 9) which in a blood-free pressure gauge chamber (3) measures changes in the conveyor pressure which appear depending on the reactions of the blood to be examined which have taken place in the reaction device (39), a blood collection chamber (10) for collecting the blood transported through the reaction device (39), the pressure gauge chamber (3) being situated below the storage chamber (15) and above the surface of the blood which is led through the reaction device (39) into the blood collection chamber (10), the conveyor pressure in a pressure-sealed working chamber (12) being generated by a piston-cylinder system (1), a working surface (33) of the piston (4) forming a boundary of the working chamber (12), and the working chamber (12) being formed by the blood collection chamber (10) and the blood-free pressure gauge chamber (3).
 2. Device for examining the properties of the global, in particular the primary, hemostasis functions in whole blood or platelet-rich plasma, comprising a storage chamber (15) for the blood to be examined, a reaction device (39) having at least one flow path (5, 7, 11, 16) via which blood to be examined is transported for carrying out certain reactions, a conveyor device (1) which conveys a volumetric flow for the transport of the blood through the reaction device (39), thereby generating a conveyor pressure in a working chamber (12), a pressure gauge (8, 9) which in a blood-free pressure gauge chamber (3) measures changes in the conveyor pressure which appear depending on the reactions of the blood to be examined which have taken place in the reaction device (39), a blood collection chamber (10) for collecting the blood transported through the reaction device (39), the pressure gauge chamber (3) being situated below the blood collection chamber (10) and above the surface of the blood to be transported through the reaction device (39), the conveyor pressure in a pressure-sealed working chamber (12) being generated by a piston-cylinder system (1), a working surface (33) of the piston (4) forming a boundary of the working chamber (12), and the working chamber (12) being formed by the storage chamber (15) and the blood-free pressure gauge chamber (3).
 3. Device for examining the properties of the global, in particular the primary, hemostasis functions in whole blood or platelet-rich plasma, comprising a storage chamber (15) for the blood to be examined, a reaction device (39) having at least one flow path (5, 7, 11, 16) via which blood to be examined is transported for carrying out certain reactions, a conveyor device (36) which conveys a volumetric flow for the transport of the blood through the reaction device (39), thereby generating a conveyor pressure, a pressure gauge (8, 9) which in a blood-free pressure gauge chamber (3) measures changes in the conveyor pressure which appear depending on the reactions of the blood to be examined which have taken place in the reaction device (39), a pressure-sealed blood collection chamber (10) for collecting the blood transported through the reaction device (39), the pressure gauge chamber (3) being situated below the storage chamber (15) and above the surface of the blood which is led through the reaction device (39) into the pressure-sealed blood collection chamber (10), the conveyor pressure being generated by a piston-cylinder system (36), a working surface (33) of the piston (4) forming a boundary of the working chamber (12), and the working chamber (12) being connected to the blood-free pressure gauge chamber (3) via a pressure line (8).
 4. Device according to one of claims 1 or 2, characterized in that the pressure gauge chamber (3) is formed by a portion of the reaction device (39) and the cylinder (25) of the piston-cylinder system (1).
 5. Device according to one of claims 1 through 4, characterized in that the piston-cylinder system (1) is formed by a syringe.
 6. Device according to one of claims 1 through 5, characterized in that the pressure is detectable in the pressure gauge chamber (3) using a pressure line (8) introduced in a leak-tight manner into the pressure gauge chamber (3).
 7. Device according to one of claims 1 through 5, characterized in that the pressure line (8) is designed as a hollow needle and is guided through a wall (37) or a sealing insert (26) in the pressure gauge chamber (8).
 8. Device according to one of claims 1 through 7, characterized in that the piston-cylinder system (36) designed as a withdrawal syringe is connectable to the reaction device (39) via a hollow needle (43; 55).
 9. Device according to claim 8, characterized in that the hollow needle (55) is provided on the reaction device.
 10. Device according to one of claims 1 through 9, characterized in that the storage chamber (15) is formed in a withdrawal syringe.
 11. Device according to claim 6 or 7, characterized in that the pressure line (8) is connected to a pressure gauge (9).
 12. Device according to one of claims 1 through 11, characterized in that the piston-cylinder system (1) is integrated into a housing (38) which includes a blood collection chamber (10).
 13. Device according to one of claims 1 through 12, characterized in that the conveyor device (36) is led into the collection chamber (10), which also includes the pressure gauge chamber (3), via the pressure-sealed pressure line (8) which is guided through the wall (37).
 14. Device according to one of claims 1 through 13, characterized in that the pressure line (8) is designed with a tapering end (42) and projects into the pressure gauge chamber (3) through the container wall (37), or through the boundary wall of a withdrawal syringe (45), or through the wall of a syringe adapter (22), or through the sealing insert (26) of the withdrawal syringe (45).
 15. Device according to one of claims 1 through 14, characterized in that the piston-cylinder system (1; 36) is driven by an electrically operated drive device (17).
 16. Device according to one of claims 1 through 15, characterized in that the piston (4) may be moved back and forth under the measurement conditions, with the result that the blood to be measured is led through the reaction device from different directions.
 17. Device according to one of claims 1 through 16, characterized in that the piston (4) is connectable to the drive device (17) via a detachable coupling (13).
 18. Device according to one of claims 1 through 17, characterized in that a pressure gauge line (41) connected to the pressure sensor (9) is branched from the pressure line (8) between the piston-cylinder system (36) and the end of the pressure line (8) which is guided into the pressure gauge chamber (3).
 19. Device according to one of claims 1 through 18, characterized in that the reaction device (39) is situated above the blood collection chamber (10) in a common housing (38) which includes the blood collection chamber (10).
 20. Device according to one of claims 1 through 19, characterized in that the storage chamber (15) is situated above or below the reaction device (39).
 21. Device according to one of claims 1 through 20, characterized in that the storage chamber (15) is situated in the common housing (38) or in a separate housing.
 22. Device according to one of claims 1 through 21, characterized in that the reaction device (39) is insertable in a liquid-sealed manner into the common housing (38) or separate housing, or is situated in a liquid-sealed manner in the common housing (38).
 23. Device according to one of claims 1 through 22, characterized in that a hollow needle (43; 55) or tube (16) is provided or can be provided between the storage chamber (15) and the reaction device (39) and/or between the reaction device (39) and the blood collection chamber (10).
 24. Device according to claim 23, characterized in that the hollow needle and/or the tube act as a feed opening and/or a shear opening.
 25. Device according to one of claims 1 through 24, characterized in that the storage chamber (15) is provided inside the cylinder of a withdrawal syringe (45) and is connectable to the reaction device (39) via the hollow needle (43; 55).
 26. Device according to one of claims 23 through 25, characterized in that the hollow needle (43) is formed by the cannula of the withdrawal syringe (45).
 27. Device according to one of claims 23 through 26, characterized in that the hollow needle (55) is attached in a pressure-sealed manner to the housing (64) which includes the reaction device (39), and with its free needle end (47) the hollow needle may be pushed in a pressure-sealed manner through a sealing wall (69) of the storage chamber (15).
 28. Device according to claim 27, characterized in that the sealing wall (69) is made of plastic or another sealing material which makes pressure-sealed contact with the hollow needle (55; 43) when the free needle end (47) is pushed through.
 29. Device according to one of claims 23 through 28, characterized in that the hollow needle (43; 55) may be pushed through the sealing insert (26) of the syringe adapter (22) or of the withdrawal syringe (45).
 30. Device according to one of claims 1 through 29, characterized in that the reaction device (39) is formed in the base region of a storage vessel (2) which includes the storage chamber (15) or blood collection chamber.
 31. Device according to one of claims 1 through 32, characterized in that the reaction device (39) has one or multiple flow openings which are designed as feed openings and/or as shear openings and/or as reaction openings.
 32. Device according to claim 31, characterized in that boundary surfaces of the respective reaction opening have a total or partial bioactive design or bioactive coating, depending on the diagnosis.
 33. Device according to one of claims 1 through 32, characterized in that the respective bioactively acting boundary surface-or, for platelets, the boundary surface capable of deposition-of a flow path or plurality of flow paths may be removed from the reaction device (39).
 34. Device according to one of claims 1 through 27, characterized in that the respective flow path is led between an outer region and a central flow opening (11) which opens into the working chamber (12) or which is connected to the storage chamber, or is led in the opposite direction.
 35. Device according to one of claims 31 or 32, characterized in that the respective flow path runs essentially horizontally.
 36. Device according to one of claims 31 through 34, characterized in that the flow path(s) run at an angle with respect to the horizontal.
 37. Device according to one of claims 1 through 36, characterized in that an insert (14) which may be removed from the storage vessel (2) is provided in order to form one or multiple boundary surfaces for the flow paths in the reaction device (39).
 38. Device according to claim 37, characterized in that a bioactive coating or a surface capable of deposition is provided on the insert (14).
 39. Device according to claim 37 or 38, characterized in that the insert (14) is made of plastic, in particular polystyrene, or glass.
 40. Device according to one of claims 1 through 39, characterized in that the base of the storage vessel (2) forms a boundary surface (30; 54) for a respective flow path in the reaction device (39).
 41. Device according to one of claims 31 through 40, characterized in that the flow paths (21) in the reaction device (39) are formed between boundary surfaces (29 and 30, 54) molded on the vessel base (31) or intermediate base (50) of the storage vessel (2) and on the insert (14).
 42. Device according to one of claims 31 through 41, characterized in that the boundary surfaces (29, 30, 54) run approximately parallel to one another.
 43. Device according to one of claims 31 through 42, characterized in that the distance between boundary surfaces (29, 30, 54) perpendicular to the direction of blood flow is significantly less than the length of the flow path.
 44. Device according to one of claims 31 through 43, characterized in that indentations, particularly in the form of impressions, are provided on at least one of the boundary surfaces (29, 30, 54) in order to form the flow paths.
 45. Device according to one of claims 31 through 43, characterized in that the reaction device (39) has one or multiple reaction openings (5, 7) whose boundary surfaces are coated with or made of a material that is bioactive or capable of deposition.
 46. Device according to claim 45, characterized in that the reaction opening (7) is formed in a film or membrane made of a bioactive material.
 47. Device according to claim 45 or 46, characterized in that the film or membrane is made of collagen or polystyrene.
 48. Device according to claim 45, characterized in that the at least one reaction opening (7) is formed in a partition (34) made of a nonporous material which is provided with a bioactive coating (35) on at least one of its two partition surfaces and/or on the respective boundary surface (6) of the reaction opening (7).
 49. Device according to one of claims 45 through 48, characterized in that the diameter of the reaction opening (7) is approximately 0.100 to 0.500 mm.
 50. Device according to one of claims 45 through 49, characterized in that a tube (16) or hollow needle (55; 43) in the reaction device (39) which acts as a feed opening and/or a shear opening is provided upstream from the reaction opening (7).
 51. Device according to one of claims 45 through 50, characterized in that a tube (16), which preferably is used as a feed tube for supplying blood to the blood collection chamber (10), is provided downstream from the reaction opening (7).
 52. Device according to one of claims 1 through 50, characterized in that a coating comprising erythrocytes and/or leucocytes, in particular of blood type 0 and/or containing von Willebrand factor, is provided in the region of the reaction opening or reaction surface.
 53. Device according to one of claims 45 through 52, characterized in that the partition (34) in which the at least one reaction opening (7) is formed has a sandwich construction.
 54. Device according to claim 53, characterized in that the partition (34) is formed from a film which is provided with a porous layer (70) on one or both sides.
 55. Device according to claim 54, characterized in that the respective porous layer (70) is coated or impregnated with a bioactive material.
 56. Method for detecting the global hemostasis function, in particular the primary hemostasis, in which blood to be examined is conveyed from a storage chamber under predetermined flow conditions through at least one reaction opening of a reaction device, and when blood components are deposited on the reaction surfaces under the action of shear forces in the at least one reaction opening, a variable pressure is measured, characterized in that the volumetric flow of the blood conveyed through the reaction device is adjusted, depending on the respective measured pressure, in such a way that the shear rate or the shear force which acts in at least one reaction opening follows a predetermined characteristic curve for the shear rate or shear force.
 57. Method according to claim 58, characterized in that the shear rate or shear force is held constant.
 58. Method according to claim 56 or 57, characterized in that the time and/or the flow volume are evaluated until a predetermined volumetric flow is reached in the reaction opening.
 59. Method according to one of claims 56 through 58, characterized in that the flow volume and/or the volumetric flow present at the time after a predetermined measurement time has elapsed, or the elapsed time for a predetermined volumetric flow and/or the volumetric flow present at the time, is/are used for the clinical evaluation.
 60. Method according to one of claims 56 through 59, characterized in that the pressure rise at the end of a predetermined time, or the time until a specified pressure is reached, is used for the clinical evaluation.
 61. Method for detecting the global hemostasis function, in particular the primary hemostasis, in which blood to be examined is conveyed from a storage chamber under predetermined flow conditions through at least one reaction opening of a reaction device, and when blood components are deposited on the reaction surfaces under the action of shear forces in the at least one reaction opening, a variable pressure is measured, in particular according to one of claims 56 through 60, characterized in that before the measurement is begun the viscosity of the blood is determined and the shear rate or shear force is adjusted, depending on said viscosity.
 62. Method according to claim 61, characterized in that the viscosity measurement is carried out in the reaction device.
 63. Method for detecting the global hemostasis function, in particular the primary hemostasis, according to one of claims 56 through 62, characterized in that the reaction device is used as a disposable part according to one of claims 1 through
 55. 